Bibliometric analysis of publications on genetic polymorphism and external apical root resorption research

ABSTRACT Objective: This study aimed to analyze the scientific production of genetic polymorphisms and external apical root resorption (EARR) to establish main findings, geographic trends, and research gaps for possible future investigations. Methods: Unrestricted publications were searched using the Scopus database (March 2023) to include studies that addressed the association between genetic polymorphisms and EARR. Case-control, cohort, cross-sectional, and review studies were considered eligible. The softwares VOS viewer™ and Bibliometrix were used for data analysis. Results: Of the 44 studies analyzed, “Iglesias-Linares A” was the most cited author. The University of Seville (Spain) conducted the most research on this topic. Brazil, Spain, and the USA were the leading countries in terms of citations. The most frequent term in the co-occurrence of keywords was “EARR.” The journal American Journal of Orthodontics and Dentofacial Orthopedics presented a great relevance in the area, demonstrating a high number of publications. Several genetic polymorphisms have been investigated, with interleukins being the most studied. Conclusion: Endodontics is an area of research that should focus more on root resorption and genetic polymorphisms, as it still underexplored, compared to orthodontics. Polymorphisms have been studied as possible predictors of EARR caused by orthodontic tooth movement. However, the gap in the research indicates a need to search for new genes associated with EARR.


INTRODUCTION
Root resorption is a local physiological process, when it occurs in healthy deciduous teeth; or pathological, when it occurs in damaged permanent and deciduous teeth.Pathological resorption may be a consequence of many factors, such as: traumatic and infectious factors, orthodontic movement and applied forces, impacted teeth, chronic bruxism, and periapical lesions. 1 Recognized as a multifactorial process that includes associated genetic factors, 2 external apical root resorption (EARR) has been investigated by several dental researchers.4][5][6][7][8][9][10] Human genetic diversity is characterized by single nucleotide polymorphisms (SNP). 115][6][7][8][9][10]12 Expanding the knowledge of EARR is essential for professionals to act coherently and scientifically to diagnose and treat it clinically.Bibliometrics is a quantitative analysis method used in Dental Press J Orthod.2024;29(4):e2423268 scientific research.The collected data reflect current research trends and help to identify topics for future research for a better understanding of scientific dynamics. 13e objective of this bibliometric review was to analyze the scientific production in the field of genetic polymorphisms and EARR to establish findings, geographic trends and research gaps for possible perspectives for future investigations.

MATERIAL AND METHODS
All analyzed data were collected from the Scopus database. 14e search was conducted in March 2023, with no limitations regarding the language or year of publication.
The following search strategy was used in this review: #1((TITLEABSKEY (genetic AND polymorphism)) AND #2 (TITLEABSKEY (root AND resorption)).The terms "external apical root resorption," "EARR," "genes," and "genetics" were tested in the primary search and no difference in the results was observed (i.e., the number of studies included was not influenced by the addition of these words).Therefore, this search key was selected because it was more sensitive to the proposed theme.
All detected studies were saved in the software (Zotero 6.0.18).
After that, the eligibility criteria was applied.Case-control, cohort, cross-sectional, and review studies that addressed the association between genetic polymorphisms and EARR were included.Case reports, book chapters, in-vitro and animal studies, and articles that mentioned only bone resorption and not root resorption were excluded.Based on these criteria, two independent reviewers (LHMP and DFSM) selected articles accessed by title and abstract.Studies with unclear abstracts and titles were read in full, to minimize the possibility of disregarding pertinent studies, and the inclusion and exclusion criteria were applied.Articles that generated disagreements between the reviewers were discussed and reviewed by a third author (LAAA), thus reaching an agreement.

BIBLIOMETRIC ANALYSIS
The softwares VOS viewer™ (version 1.6.18)for Mac 15 and Bibliometrix 16 were used for visualizing bibliometric analyses.
CSV file containing the citation and bibliographic information, abstract, and keywords was used.The VOS viewer™ software was used to analyze the characteristics of the publications, including the most cited researchers, most relevant affiliations, most cited countries, countries with the highest publication production, co-occurrence of keywords, most cited sources, most relevant authors and most cited documents, resulting in maps and graphs for visualization and interpretation of the data obtained from the analyses.The studied items were grouped into clusters, a set of items included in a map, and labeled using cluster numbers.For easier interpretation, the items were called "nodes", the links presented between them were referred to as "edges", and the strength of the links was interpreted as the "edge weight".Depending on the selected analysis, different

RESULTS
A search was conducted, and 45 articles were retrieved from the Scopus database using the search strategy.Considering the eligibility criteria, one article was unrelated to the theme.
Finally, 44 publications were retrieved and included in the bibliometric analysis (Fig 1).The larger the node, the greater the author's impact and relevance in the research field.The edges of the maps show scientific collaboration between the four clusters independently, where the red cluster is connected to the yellow and green clusters, the green cluster is connected to the red and blue clusters, and the blue and yellow clusters are not connected, showing that there is no co-authorship collaboration in this case.

ANALYSIS OF THE MAIN KEYWORDS
When analyzing the co-occurrence of keywords, we chose to analyze the keywords mentioned in the abstracts.Figure 5 enables the identification of a cloud of relevant words and acronyms.The use of the acronym EARR significantly increased the number of publications.In the field of genetics, the terms "polymorphism", "rs", and "gene" were frequent (Fig 5).
In the Figure 5, the acronym "EARR" is more prominent and larger, meaning that it appears a lot in this type of study, and it is crucial to use it if it makes sense for the author's research.
Words of the same color come close to the theme and have a strong connection between them, functioning as clusters, such as "SNPs" and "resorption" or "genetic", "EARR" and "genotype".Although less evident, interleukin was the only gene cited as a keyword in the abstracts, suggesting that it is one of the most studied genes within the topic covered.Among the most cited documents, the reference "Al-Qawasmi RA et al., 2003" 3 led the ranking, with 166 citations.Figure 7 shows the "American Journal of Orthodontics and Dentofacial Orthopedics" (appears with 4 different abbreviations) as the most cited magazine.Narrative data synthesis of the 44 included articles [2][3][4][5][6][7][8][9][10]12, are presented on Tables 1, 2 and 3. Tables 1 and 2, which provide a narrative analysis, were based on genetics and EARR studies, the most cited on orthodontics, and Table 3 presents an analysis of the reviews on the topic included in the selection.
EARR severity was assessed in the upper and lower central incisors and mesial and distal roots of the lower first molars.The analysis indicated that the IL-1B polymorphism was responsible for 15% of the total variation in upper incisor EARR.Only one of the most cited studies investigated the TaqI polymorphism of the vitamin D receptor as a possible predisposing factor for EARR. 20It is important to highlight that genes such as SPP1, P2RX7, TNFRSF11B, TNFRSF11A, [17][18][19] and the osteopontin gene cluster (rs9138 and rs11730582) 21 were also highlights of the research among the most cited articles.Another study 20 showed that different genetic polymorphisms may indicate the occurrence of EARR in individuals undergoing orthodontic treatment.The IL-1B polymorphism was not associated with an EARR predisposition, but heterogeneity among the study results was significant; however, this remains unexplained.
Although IL-1 B is considered a promising gene for predicting EARR in patients undergoing orthodontic treatment, better-controlled studies are required to verify this association.People who are homozygous for IL-1B allele 1 have an increased risk of EARR, compared to those who are not homozygous for IL-1 beta allele 1. Defining the genetic contributions to EARR is important for understanding the contribution of environmental factors, such as habits and therapeutic biomechanics (Table 1).Considering the importance of providing information that may be useful for daily clinical practice and for researchers in the field of Orthodontics, important variables were presented in   Considering the reviews on the topic, the narrative reviews of the literature highlight a series of genes studied, placing great importance on the study of interleukins. 45,46,50The systematic reviews suggest guidelines and recommendations for future researchers who study genetic polymorphism in patients undergoing orthodontic treatment, 4,24 and are not conclusive regarding the association of IL with EARR. 3,23In a meta-analysis, P2RX7 (rs208294) indicated the risk of orthodontic patients for EARR with a very low quality of evidence, according to GRADE 3 (Table 3).It is important to highlight that the level of evidence on this topic has increased over the years, culminating in the first systematic review 4 publication in 2018.A patterned increase in the number of manuscripts over the years ensures that there will also be an increase in the level of evidence presented.* Description of the most cited studies according to Figure 6.

Authors/Year Study Type Conclusion
Pinheiro et al. 3 (2021) Systematic review and meta-analyses Narrative analyses of individual studies demonstrated an association of many genes.The number of studies for each genetic variation was very low, and methodological heterogeneity between the studies was observed.The meta-analysis could only show an involvement for P2RX7 (rs208294) in the risk of orthodontic patients to EARR at a very low certainty of evidence according to GRADE *Nowrin et al.
Literature review In recent years, international research groups have determined the degree of influence of some genetic biomarkers in the definition of increased/reduced susceptibility to post-orthodontic EARR.The influences of the gene cluster IL1 (IL1B, IL1A, IL1RN, IL6), P2RX7, CASP1, OPG (TNFRSF11B), RANK (TNFRSF11A), Osteopontin (OPN), TNFa, the vitamin D receptor (TaqI), TNSALP and IRAK1 were the most analyzed Pereira et al. 46 (2018) Literature review This study was performed searching for the association of rs1800587 from Interleukin-1 alpha (IL1A) gene and rs1143634 from interleukin-1 beta (IL1B) gene with EARR.In conclusion, suggests that for IL1B SNP rs1143634 and EARR have an opposite genetic profile.For IL1A, the hypothesis could not be confirmed Behnaz et al. 502020) Concise review The rs1800587 and rs1143634 in IL-1A and IL-1B genes have been the mostly assessed SNPs in different populations.Yet, the results of investigations in different populations are not consistent.In this study, the authors summarize the results of studies that assessed the contribution of genetic factors in EARR.As genetic factors are involved in conferring risk of EARR, evaluation of these variants prior to establishment of orthodontic treatments might help in identification of at-risk individuals and better follow-up of these patients

DISCUSSION
Dentistry research needs to be constantly updated for clinical practice.Metric studies such as bibliometric reviews allow the analysis of scientific production to obtain results that bring, in addition to quantitative data, possibilities for qualitative and representative analyses of various areas of knowledge. 51,52e practice of evidence-based Dentistry helps highlight the importance of each study design because there is an appropriate delineation capable of answering each clinical question.
The main goal is to help clinicians perform more effective, efficient, and predictable treatments and make decisions based on robust scientific evidence and patient behavior.In this case, we noticed the tendency for publications of reviews, concise reviews, systematic reviews and meta-analyses on the topic. 3,4,23,24,45,46,50In this bibliometric analysis, we can observe its peculiarities and observe the significant increase in scientific evidence concerning the topic presented over the years.Before starting a systematic review, one should identify its real need, through the search for secondary studies with the same theme and objective.So a bibliometric analysis presents fundamental importance for to be able to evaluate a general panorama on the subject researched and to visualize the interaction of other studies of their interest, in addition to expanding the possibilities of access to other articles in the area. 52rthermore, as EARR is unpredictable and depends on multiple factors, it is extremely important to carry out a careful and complete diagnosis through history and periapical radiographic examinations, so that rational mechanotherapy can be planned.This must be accessed based on literature, and bibliometrics can be a quantitative method for accessing existing scientific research.

MAIN FINDINGS
Regarding collaboration between authors, organizations, and countries, the USA is dominant since most of the high-impact scientific journals are North American; however, the presence of Brazil also indicates that the intellectual production of Brazilian researchers has significant scope in the international scene.The journals "American Journal of Orthodontics and Dentofacial Orthopedics", "Oral Diseases", "The Angle Orthodontist", and "European Journal of Orthodontics" are of great relevance in the area, demonstrating a high number of publications on the subject and a great impact factor within the literature.Highly productive researchers such as Iglesias-Linares A, Flores-Mir C, Hartsfield J K, and Al-Qawasmi RA formed a group of reference authors.
With scientific mapping, it is also possible to monitor temporal evolution and identify the main authors involved. 52In addition, the notable network of researchers over the years has been less concentrated on just one specific author, as in 2008 and 2009, when studies on polymorphisms and EARR were concentrated on Al-Qawasmi RA 5,27 and Bastos Lages. 6 this bibliometric analysis, authors such as Iglesias-Linares A, genes involved in EARR susceptibility due to orthodontic tooth movement.The same study found, in the individual analysis of articles, that interleukins were more strongly associated with EARR; however, in the meta-analyses, by increasing the statistical power by grouping the studies, this finding was not confirmed.This result is consistent with a previous study by Nowrin et al. 4 , in which it was suggested that the IL-1B polymorphism is not associated with a predisposition to EARR in their meta-analysis.Therefore, the current evidence highlights a gap in the research, suggesting the need for larger multicenter studies to investigate new genes associated with EARR.

CONCLUSIONS
Based on the bibliometric analysis, it is concluded that there are still few research groups that explore this topic, with the studies being most explored in Spain, Brazil and the USA.
Endodontics is an area of research that could focus more on root resorption and genetic polymorphisms, as it still underexplored compared to Orthodontics.Polymorphisms have been studied as possible predictors of EARR caused by orthodontic tooth movement.However, there is still a gap in research, indicating the need to search for new genes associated with EARR.
nodes represented different terms, and their sizes indicated the number of citations, co-citations, and co-occurrences of keywords.The nodes and lines belonging to the same cluster had the same color.A network visualization map of the most cited researchers, network visualization map of the most cited countries, most cited documents, and timeline of the corresponding publications was generated in the VOS viewer™.Bibliometrix software is an open-source tool that covers a range of quantitative analyses, favoring the visualization of the results.Maps and graphs were generated, and data matrices were constructed for co-citation, scientific collaboration, and keyword analyses.The synthesis of relevant narrative data (data extraction) was independently done by two reviewers (LHMP and DFSM).It was presented in detail, and grouped by year of publication.The data of the selected articles were allocated and organized in tables:

Figure 1 :
Figure 1: Flow diagram of the selection process.

Pinheiro
LHM, Moura DFS, Antunes LS, Antunes LAA -Bibliometric analysis of publications on genetic polymorphism and external apical root resorption research Dental Press J Orthod.2024;29(4):e2423268 MAIN RESEARCH CENTERS Research centers related to the topic were identified, with the five most relevant centers being: the University of Seville (Spain), Pontifical Catholic University of Paraná (Brazil), University of Coimbra (Portugal), Federal University of Minas Gerais (Brazil) and Masaryk University (Czech Republic) (Fig 3).

Figure 2 :
Figure 2: Network visualization map of the most cited researchers.

Figure 4 :B
Figure 4: A) Network visualization map of top countries regarding citation.B) Global visualization map of the countries that search the most on the topic.The darker the shade of blue, the more intense the scientific collaboration within the theme, with the countries shown in navy blue being the most prominent in this area of research as well.

Figure 5 :
Figure 5: Word cloud for analysis of the co-occurrence of keywords in the abstract.

Figure 6 :
Figure 6: Global visualization of the most cited documents.

Figure 7 :
Figure 7: Global visualization of the most cited sources (journal).

Figure 8 :
Figure 8: Global visualization of the most relevant authors.

Figure 9 :
Figure 9: Global visualization of the most relevant authors and the timeline of corresponding publications.

Pinheiro LHM,and external apical root resorption research 30 Dental
Moura DFS, Antunes LS, Antunes LAA -Bibliometric analysis of publications on genetic polymorphism

Flores-
Mir C, Hartsfield JK, and Al-Qawasmi RA formed a prominent group in the scientific literature on the subject.The first author to be highlighted is Iglesias-Linares A, and the map of the visualization network shows the author with a large node in the red cluster.However, it is possible to see that the clusters of authors are interconnected subtly, without showing great support or partnerships, suggesting that these studies Dental Press J Orthod.2024;29(4):e2423268

Table 1 -
Description of the selected studies about genetic polymorphisms associated to EARR; Table2-sample characteristics of the most cited studies in the field of orthodontics; and

Table 3 -
analyses of revisions included in the bibliometrics.

Table 1 :
Description of the selected studies about genetic polymorphisms associated to EARR.

Table 1 :
(Continuation) Description of the selected studies about genetic polymorphisms associated to EARR.

Table 1 :
(Continuation) Description of the selected studies about genetic polymorphisms associated to EARR.

Table 2 :
Sample characteristics of the most cited studies of the Orthodontics area.

Table 2 ,
regarding the most cited orthodontic studies, such as: study design, study population, sample size, average age, EARR assessment methods, teeth selected for EARR assessment, orthodontic technique used and Angle classification.

Table 2 :
(Continuation) Sample characteristics of the most cited studies of the Orthodontics area.

Table 2 :
(Continuation) Sample characteristics of the most cited studies of the Orthodontics area.

Table 3 :
Analysis of revisions included in the bibliometrics.